US3738979A - O2,2'-cyclocytidine-3'-phosphate and process for producing same - Google Patents
O2,2'-cyclocytidine-3'-phosphate and process for producing same Download PDFInfo
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- US3738979A US3738979A US00868913A US3738979DA US3738979A US 3738979 A US3738979 A US 3738979A US 00868913 A US00868913 A US 00868913A US 3738979D A US3738979D A US 3738979DA US 3738979 A US3738979 A US 3738979A
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- phosphate
- cyclocytidine
- aracytidine
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- producing same
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- 238000000034 method Methods 0.000 title description 12
- 229910019142 PO4 Inorganic materials 0.000 abstract description 27
- 239000010452 phosphate Substances 0.000 abstract description 27
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract description 25
- 150000001875 compounds Chemical class 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 239000011347 resin Substances 0.000 description 7
- 229920005989 resin Polymers 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Natural products NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000007792 addition Methods 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 3
- 229940104302 cytosine Drugs 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical class CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- NMPZCCZXCOMSDQ-ZRTZXPPTSA-N Cytidine 2',3'-cyclic phosphate Chemical compound O=C1N=C(N)C=CN1C1[C@@H]2OP(O)(=O)O[C@@H]2[C@@H](CO)O1 NMPZCCZXCOMSDQ-ZRTZXPPTSA-N 0.000 description 1
- 125000003319 D-arabinosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O)CO1)* 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000003327 cancerostatic effect Effects 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- ZTQSADJAYQOCDD-UHFFFAOYSA-N ginsenoside-Rd2 Natural products C1CC(C2(CCC3C(C)(C)C(OC4C(C(O)C(O)C(CO)O4)O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC(C(C(O)C1O)O)OC1COC1OCC(O)C(O)C1O ZTQSADJAYQOCDD-UHFFFAOYSA-N 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
Definitions
- O ,2-cyclocytidine-3' phosphate is a potential drug per se and also an important intermediate in the synthesis of several potential drugs, for example, polyarabinocytidylates.
- the antileukemic activity of O ,2'-cyclocytidine-3 phosphate has been tested on mice and has been found to have approximately the same therapeutic index as arabinosylcytosine (ara-C) which has a similar structure.
- the procedure for synthesizing O ,2'-cyclocytdine-3 phosphate also can be used to synthesize aracytidine-3 phosphate which exhibits an activity similar to 1-B-D- arabinocyl cytosine (Smith et al., J. Med.
- O ,2-cyclocyti dine-3' phosphate is converted to arabinosylcytosine (ara- C) in viyo. This has been determined by experiments with the compound in human blood.
- O ,2'-cyclocytidine-3 phosphate can be administered orally to mice.
- Purification may be accomplished by dissolving the resin in cold water, adjusting the pH to 5.5 with pyridine and passing the resulting solution through a Dowex 1-X2 (acetate) resin column. The effluent is freeze-dried and the residue extracted with ether and crystallized from wateracetone. A number of modifications of the isolation and purification procedure are feasible. For example, the product may be obtained without ion exchange filtration by merely precipitating and crystallizing the product, although a lower yield is thus obtained.
- Any non-protolytic solvent may be used in this process.
- Suitable solvents include pyridine, dioxane, dimethyl formamide, dimethylsulfoxide, etc.
- Other trimethylsilylating agents other than trimethylsilyl chloride may also be used with the exception of hexamethyl disilazane.
- any trialkylsilyl and dialkylsilyl donor is suitable which does not generate ammonia or primary amines. Concentration of the reactants is not critical, merely an excess of silylating agent and base is necessary. A wide range of temperatures from 40120 C. can be employed with appropriate changes in reaction time.
- Aracytidine-3 phosphate can be obtained by titrating 0 ,2 cyclocytidine-3' phosphate with dilute NaOH or KOH to pH 10. This produces a quantitative conversion of the starting material to aracytidine-3 phosphate.
- Aracytidine-3' phosphate can also be obtained directly by using the procedure for the preparation of O ,2'-cyclocytidine-3' phosphate in which case instead of stirring the reaction mixture with ice alone (step 3) the reaction mixture is poured into a mixture of KOH and ice.
- the solution is passed through a 20 ml. Dowex 1-X2 (acetate) resin column.
- the resin is washed with 50 ml. water at 5 C. and the efiluent freeze dried.
- the residue is extracted with water and then crystallized from water-acetone (2.1 g.). Additional amounts of the product were obtained by eluting the resin with 0.02 M acetic acid (0.3 g.).
- the product migrates as a homo genous spot on electrophoresis in 0.03 M phosphate, pH 7.0; mobility 0.8 relative to cytidine-2,3-cyclic phosphate.
- Paper chromatographic mobility in ethanol-0.5 M ammonium acetate (pH 7) 5:2 is identical to cytidine-2'(3)- phosphate. Upon recrystallization from water-acetone and drying at room temperature, 0.01 mm. for 8 hours over P the elementary analysis gave C, 33.47; H, 4.44; N, 12.90; P, 9.8% (by titration) calculated for (cm- 1665, 1376, 1358, 1252, 1212, d060, 932.
- a process for preparing O ,2-cyclocytidine-3 phosphate which consists essentially of heating a mixture of cytidine-2,3 cyclic phosphate in the form of its tri-nbutyl ammonium salt in a non-protolytic solvent with an excess of a tertiary organic base to a temperature of 40 C. while adding an excess of a lower alkyl silylating agent, cooling the mixture and recovering the crystalline product.
- a process for preparing aracytidine-3' phosphate by thermal conversion which consists essentially of heating a mixture of cytidine-2,3 cyclic phosphate in the form of its tri-n-butyl ammonium salt in a non-protolytic solvent with an excess of a tertiary organic base to a temperature of 40-120 C. while adding an excess of a lower alkyl silylating agent, cooling the mixture, adding a strong inorganic base until the pH of the mixture is 13, and recovering the crystalline product.
- non-protolytic solvent is selected from the group consisting of pyridine, dioxane, dimethyl formamide, and dimethyl sulfoxide.
- a process for preparing aracytidine-3' phosphate which consists essentially of titrating O ,2'-cyclocytidine- 3' phosphate with a strong inorganic base to a pH of 10 and recovering the crystalline product.
- said strong inorganic base is selected from the group consisting of NaOH and KOH.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A NOVEL PROCESS FOR PREPARING O2,2''-CYCLOCYTIDINE-3'' PHOSPHATE, A NEW COMPOUND, AND ARACYTIDINE-3'' PHOSPHATE, A KNOWN COMPOUND, IS DESCRIBED.
Description
United States Patent 3,738,979 O ,2-CYCLOCYT!DINE-3-PHOSPHATE AND PROCESS FOR PRODUCING SAME Joseph Nagyvary, Byran, Tex., assignor to the United States of America as represented by the Secretary,
Department of Health, Education, and Welfare No Drawing. Filed Oct. 23, 1969, Ser. No. 868,913 Int. Cl. C07d 51/52 US. Cl. 260-2115 9 Claims ABSTRACT OF THE DISCLOSURE A novel process for preparing O ,2-cyclocytidine-3' phosphate, a new compound, and aracytidine-3 phosphate, a known compound, is described.
In one of the major procedures leading to 1-,8 D-arabinosyl cytosine (Walwick et al., Proc. Chem. Soc., 84 (1959) O ,2-cyclocytidine-3,5'-diphosphate appears as an intermediate. The significance of 1-18 D-arbinosyl cytosine as a carcinostatic and anti-viral agent is well documented (Hunter, U.S. Pat. No. 3,116,282) and (Cohen, S. 8., Progress in Nucleic Acid Research and Molecular Biology, Academic Press, New York, vol. 5, p. 2 (1966).
However, O ,2-cyclocytidine-3' phosphate is a potential drug per se and also an important intermediate in the synthesis of several potential drugs, for example, polyarabinocytidylates. The antileukemic activity of O ,2'-cyclocytidine-3 phosphate has been tested on mice and has been found to have approximately the same therapeutic index as arabinosylcytosine (ara-C) which has a similar structure. The procedure for synthesizing O ,2'-cyclocytdine-3 phosphate also can be used to synthesize aracytidine-3 phosphate which exhibits an activity similar to 1-B-D- arabinocyl cytosine (Smith et al., J. Med. Chem, :10, 774 (1967). It is also important to note that O ,2-cyclocyti dine-3' phosphate is converted to arabinosylcytosine (ara- C) in viyo. This has been determined by experiments with the compound in human blood. O ,2'-cyclocytidine-3 phosphate can be administered orally to mice.
The basic concept underlying the synthesis of the new compound O ,2 cyclocytidine-3 phosphate is the thermal rearrangement of fully dialkyl or trialkylsilylated cytidine-2,3-cyclic phosphate.
HlyISiMea MeSiO CH I II PREPARATION OF O ,2'-CYCLOCYTIDINE3 PHOSPHATE (FORMULA II) HOCHz O SiMes ice (5) Evaporate the aqueous phase in vacuo in the cold under repeated additions and evaporation of the nonprotolytic solvent.
(6) Extract the resulting resin with ether and purify.
Purification may be accomplished by dissolving the resin in cold water, adjusting the pH to 5.5 with pyridine and passing the resulting solution through a Dowex 1-X2 (acetate) resin column. The effluent is freeze-dried and the residue extracted with ether and crystallized from wateracetone. A number of modifications of the isolation and purification procedure are feasible. For example, the product may be obtained without ion exchange filtration by merely precipitating and crystallizing the product, although a lower yield is thus obtained.
Any non-protolytic solvent may be used in this process. Suitable solvents include pyridine, dioxane, dimethyl formamide, dimethylsulfoxide, etc. Other trimethylsilylating agents other than trimethylsilyl chloride may also be used with the exception of hexamethyl disilazane. In general, any trialkylsilyl and dialkylsilyl donor is suitable which does not generate ammonia or primary amines. Concentration of the reactants is not critical, merely an excess of silylating agent and base is necessary. A wide range of temperatures from 40120 C. can be employed with appropriate changes in reaction time.
PREPARATION OF ARACYTIDINE-3' PHOSPHATE (FORMULA III) Aracytidine-3 phosphate can be obtained by titrating 0 ,2 cyclocytidine-3' phosphate with dilute NaOH or KOH to pH 10. This produces a quantitative conversion of the starting material to aracytidine-3 phosphate. Aracytidine-3' phosphate can also be obtained directly by using the procedure for the preparation of O ,2'-cyclocytidine-3' phosphate in which case instead of stirring the reaction mixture with ice alone (step 3) the reaction mixture is poured into a mixture of KOH and ice.
Example I.Preparation of O ,2'-cyclocytidine-3 phosphate Cytidine-2',3'-cyclic phosphate obtained from 3.3 g. (10 moles) of 2'(3)-cytidylic acid by any of the usual methods, for example according to Michelson (J. Chem. Soc., 3655 (1959), in the form of its tri-n-butyl ammonium salt, is dissolved in a mixture of 10 ml. pyridine and 10 NHZ III
ml. tri-n-butylamine. This solution is heated to C. under the dropwise addition of 6 ml. of trimethylsilyl chloride during five minutes, whereafter it is heated for another thirty minutes. The solution is concentrated to half in vacuo and stirred with about 30 g. of ice for 10 minutes. The excess base is extracted with two 30 ml. portions of petroleum ether and the aqueous phase evaporated in vacuo in the cold under repeated additions and evaporation of dry pyridine. The resulting gum is exextracted three times with 30 ml. ether, dissolved in cold water and, after the pH is adjusted to 5.5 with pyridine,
the solution is passed through a 20 ml. Dowex 1-X2 (acetate) resin column. The resin is washed with 50 ml. water at 5 C. and the efiluent freeze dried. The residue is extracted with water and then crystallized from water-acetone (2.1 g.). Additional amounts of the product were obtained by eluting the resin with 0.02 M acetic acid (0.3 g.). The product thus obtained migrates as a homo genous spot on electrophoresis in 0.03 M phosphate, pH 7.0; mobility 0.8 relative to cytidine-2,3-cyclic phosphate. Paper chromatographic mobility in ethanol-0.5 M ammonium acetate (pH 7) 5:2 is identical to cytidine-2'(3)- phosphate. Upon recrystallization from water-acetone and drying at room temperature, 0.01 mm. for 8 hours over P the elementary analysis gave C, 33.47; H, 4.44; N, 12.90; P, 9.8% (by titration) calculated for (cm- 1665, 1376, 1358, 1252, 1212, d060, 932. Char- H acteristic NMR frequencies (D 0): H6 8.61 (1:75 c.p.s.), H-5 7.09 (7.5), H1 715 (5.5) and H-2 6.24 (5.5) ppm.
Example IL-Preparation of aracytidine-3' phosphate from 0 ,2'-cyclocytidine-3 phosphate When O ,2'-cyclocytidine-3' phosphate is titrated with dilute NaOH or KOH to pH 10, a quantitative conversion to aracytidine-3' phosphate (Formula III) takes place. On electrophoresis at pH 7 and in several paper chromatographic systems, aracytidine-3 phosphate is indistinguishable from cytidine-2,(3) phosphate. The zwitter-ionic form can be obtained by absorbing the dianionic form on Dowex 1-X8 (formate) resin, eluting with dilute (0.05 N) formic acid and subsequent freeze drying. The UV spectrum at pH 4.5 shows a at 274 m (e=10,600), and at pH 1 X at 279 my. (e==13,800). Characteristic NMR signals (p.p.m., D 0): H-6 8.49 (J =8 c.p.s.), H-5 6.66 (J=8) and H-1 6.60 (1:3); spectrum taken on Varian HA100 instrument at 100 mHz. with tetramethyl silane as external standard.
Example IIL-Prcparation of aracytidine-S' phosphate directly The thermal conversion is carried out as described in Example I for the preparation O ,2-cyclocytidine-3 phosphate, but instead of the addition of ice alone the reaction mixture is slowly mixed with a mixture of ice and KOH. The resulting solution (pH 13) is applied to a 2.5 x 30 cm. Dowex 1-X8 (formate) column, washed with water and eluted with 0.02 N formic acid. Aracytidine-3 Cir phosphate was obtained in yield based on cytidine- 2',3-cyclic phosphate.
1 claim:
1. O ,2-cycloeytidine-3' phosphate.
2. A process for preparing O ,2-cyclocytidine-3 phosphate which consists essentially of heating a mixture of cytidine-2,3 cyclic phosphate in the form of its tri-nbutyl ammonium salt in a non-protolytic solvent with an excess of a tertiary organic base to a temperature of 40 C. while adding an excess of a lower alkyl silylating agent, cooling the mixture and recovering the crystalline product.
3. The process of claim 2 wherein said non-protolytic solvent is selected from the group consisting of pyridine, dioxane, dimethyl formamide and dimethyl sulfoxide.
4. The process of claim 3 wherein said alkyl silylating agent is trimethylsilyl chloride.
5. A process for preparing aracytidine-3' phosphate by thermal conversion which consists essentially of heating a mixture of cytidine-2,3 cyclic phosphate in the form of its tri-n-butyl ammonium salt in a non-protolytic solvent with an excess of a tertiary organic base to a temperature of 40-120 C. while adding an excess of a lower alkyl silylating agent, cooling the mixture, adding a strong inorganic base until the pH of the mixture is 13, and recovering the crystalline product.
6. The process of claim 5 wherein said non-protolytic solvent is selected from the group consisting of pyridine, dioxane, dimethyl formamide, and dimethyl sulfoxide.
7. The process of claim 6 wherein said lower alkyl silylating agent is trimethylsilyl chloride.
8. A process for preparing aracytidine-3' phosphate which consists essentially of titrating O ,2'-cyclocytidine- 3' phosphate with a strong inorganic base to a pH of 10 and recovering the crystalline product.
9. The process of claim 8 wherein said strong inorganic base is selected from the group consisting of NaOH and KOH.
References Cited UNITED STATES PATENTS 8/1969 Nagyvary 260-2115 R 8/1969 Shen et al 260-2115 R OTHER REFERENCES LEWIS GOTTS, Primary Examiner J. R. BROWN, Assistant Examiner US. Cl. X.R.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US86891369A | 1969-10-23 | 1969-10-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3738979A true US3738979A (en) | 1973-06-12 |
Family
ID=25352550
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US00868913A Expired - Lifetime US3738979A (en) | 1969-10-23 | 1969-10-23 | O2,2'-cyclocytidine-3'-phosphate and process for producing same |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3738979A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2413938A4 (en) * | 2009-03-12 | 2012-12-12 | Univ Florida | KINASEPROTEINBINDENDE HEMMER |
-
1969
- 1969-10-23 US US00868913A patent/US3738979A/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2413938A4 (en) * | 2009-03-12 | 2012-12-12 | Univ Florida | KINASEPROTEINBINDENDE HEMMER |
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